Uses of myostatin antagonists, combinations containing them and uses thereof

ABSTRACT

The present invention relates to myostatin antagonists, for the treatment of cancer cachexia, and cancer cachexia due to chemotherapeutic treatment Especially, the myostatin antagonist bimagrumab was found to be beneficial in the treatment of cancer cachexia by reducing body weight loss. The present invention also relates to combinations and uses of a myostatin antagonist and an mTOR inhibitor for treating cancer cachexia by reducing, maintaining or increasing body weight loss or for use in treating age-related conditions.

FIELD OF THE INVENTION

The present disclosure relates to the use of myostatin or activinantagonists and in particular of activin type II (ActRII) receptorinhibitors in the treatment of cancer cachexia.

The invention relates more specifically to combinations comprising (a)an activin type II receptor (ActRII) inhibitor and (b) achemotherapeutic agent or a pharmaceutically acceptable salt thereof,for simultaneous, separate or sequential use, uses thereof, or methodsof treatment using it, in the treatment of cancer cachexia.

The disclosure also relates to combinations uses thereof of a myostatinantagonist and an mTOR inhibitor. Such a combined uses are for use incancer cachexia and for age-related conditions.

BACKGROUND OF THE INVENTION

Cachexia affects the majority of patients with advanced cancer and isassociated with a poor outcome, a reduction in treatment tolerance,response to therapy, quality of life and duration of survival. Skeletalmuscle loss appears to be the most significant event in cancer cachexiaand cannot be fully reversed by conventional nutritional support [Fearonet al 2011, Tan et al 2009]. Recently, it has been shown in mouse modelsof ectopic lung and colon cancer, that direct myostatin inhibition witha monoclonal antibody as well as indirect inhibition using a solubleActRIIB-Fc protects from muscle wasting and even extends survival [BennyKlimek et al 2010, Busquets et al 2012, Murphy et al 2011, Zhou et al2010].

Several members of the transforming growth factor beta (TGF-β)superfamily, including myostatin, Activin A, and growth differentiationfactor 11 (GDF-11), are known to negatively regulate skeletal musclemass in animals and humans throughout the lifecycle. The mechanism ofmyostatin signaling is complex due to activation of several downstreampathways [Elkina et al 2011]. Myostatin, Activin and GDF-11 bind toactivin type II receptors (ActRII) and induce its assembly with activintype I receptor. The absence of myostatin in developing animals andhumans results in a hyper-muscular phenotype with an increased numberand size of muscle fibers [Lee and McPherron 2001, Schuelke et al 2004].Similarly, inhibition of myostatin action in adult animals increasesmuscle mass, suggesting that myostatin also restrains skeletal musclemass in adulthood [Whittemore et al 2003, Lee et al 2005, Nakatani et al2008]. In contrast, high levels of myostatin or Activin A have beenreported to promote cachexia and the subsequent muscle wasting [Zimmerset al, 2002; Chen et al, 2014].

WO07/067616 shows the reduction of weight loss by the administration ofa myostatin-binding agent such as a peptide binding myostatin in normalmice treated with 5-fluorouracil. However it does not show that thepeptide binding myostatin reduces body weight loss or increases the bodyweight in tumor-bearing model mice such as CT-26, either in the absenceof or with a treatment using anticancer agents as demonstrated accordingto the present disclosure.

Bimagrumab is a human monoclonal antibody developed to bindcompetitively to ActRII with greater affinity than its natural ligandsmyostatin and activin A. It induces skeletal muscle hypertrophy andprotects from dexamethasone-induced atrophy in mice [Lach-Trifilieff etal 2014] and is shown to improve the disease condition in the patientssuffering from sporadic inclusion body myositis without causing seriousadverse events [Amato et al 2014]. Although it has been shown that thepharmacological blockade of ActRII pathway using a soluble receptorantagonist protects from cancer-induced cachexia in mice [Busquets et al2012, Zhou et al 2010], cachectic patients with advanced cancer willlikely receive anti-cancer agents against their specific cancer type asa standard of care, and whether ActRII inhibition remains efficaciouswhen combined with anti-cancer agents has not been elucidated yet.

According to the present invention, the effect of a chimeric mouseversion of bimagrumab, which is shown to retain the binding, selectivityand potency profile of bimagrumab while reducing risk for immunogenicityand enabling long-term profiling studies in mice, was evaluated in aCT-26 mouse colon cancer cachexia model to clarify interactions betweenbimagrumab and chemotherapies. Additionally, intervention at the Activintype II receptors level via the use of the neutralizing Ab bimagrumab iseffective at protecting from cancer-induced cachexia as reported earlierthrough the blockade of circulating ligands (anti myostatin Ab orsoluble ActRIIB-Fc).

Platinum-based drugs, such as cisplatin, are cytotoxic, intercalatingagents that prevent DNA replication in a very unspecific manner andwhich are typically used as first-line therapy. Problematically,cisplatin has been shown to precipitate body and muscle weight loss as aside effect. We thus first aimed at evaluating the potential ofbimagrumab in countering cisplatin-mediated effects on muscle wasting.In a follow-up study, the impact of a more frequent dose of bimagrumaband everolimus, a new generation, less cytotoxic, molecular-targetedagent, which inhibits the mammalian target of rapamycin (mTOR), oncancer cachexia was then assessed.

In addition, loss of muscle mass and attendant loss of total body water(as part of the cachexia pathophysiology) leads to a smaller volume ofdistribution for chemotherapeutic agents [Parsons 2012]. This in turncauses a higher concentration (Cmax and AUC) of these cytotoxic agents,leading to more adverse events and poorer chemotherapy tolerance incachectic patients than in noncachectic cancer patients [Sjoblom 2015,Arrieta 2015]. A manifestation of this invention is that it can lead tobetter chemotherapy tolerance, more effective anti-cancer treatment, andbetter outcomes (including progression-free survival and overallsurvival) than with anti-cancer treatment alone in patients with cancercachexia.

Currently, there is no standard treatment for cancer cachexia.

Therefore, pharmacotherapeutics that can reduce or prevent body weightloss or even increase body weight in the context of cancer, with orwithout treatment with chemotherapeutic agents, and in particular withmTOR inhibitors are highly desired.

In addition the combination of a myostatin or activin antagonist and ofan mTOR inhibitor according to the present disclosure has also thepotential to treat age-related conditions.

SUMMARY OF THE INVENTION

A first subject matter of the present disclosure therefore relates to acombination of an ActRII receptor inhibitor and a chemotherapeutic agentfor treating cancer cachexia.

Another subject matter of the disclosure therefore relates methods oruses for treating cancer cachexia of compositions comprising a myostatinor activin antagonist, which can be a myostatin binding molecule or anActRII binding molecule.

According to the present disclosure, the effect of a chimeric mouseversion of bimagrumab, which is shown to retain the binding, selectivityand potency profile of bimagrumab while reducing risk for immunogenicityand enabling long-term profiling studies in mice, was evaluated in aCT-26 mouse colon cancer cachexia model to clarify interactions betweenbimagrumab and chemotherapies. Additionally, intervention at the Activintype II receptors level via the use of the neutralizing Ab bimagrumab iseffective at protecting from cancer-induced cachexia as reported earlierthrough the blockade of circulating ligands (anti myostatin Ab orsoluble ActRIIB-Fc).

Platinum-based drugs, such as cisplatin, are cytotoxic, intercalatingagents that prevent DNA replication in a very unspecific manner andwhich are typically used as first-line therapy. Problematically,cisplatin has been shown to precipitate body and muscle weight loss as aside effect. It was first aimed at evaluating the potential ofbimagrumab in countering cisplatin-mediated effects on muscle wasting.In a follow-up study, the impact of a more frequent dose of bimagrumaband everolimus, a new generation, less cytotoxic, molecular-targetedagent, which inhibits the mammalian target of rapamycin (mTOR), oncancer cachexia was then assessed.

Muscle Regulation and the ActRII Receptors

Several members of the transforming growth factor beta (TGF-β)superfamily, including myostatin, activin A, and growth differentiationfactor 11 (GDF11), negatively regulate skeletal muscle mass in animalsand humans throughout the lifecycle. Ligand signaling occurs via type IIactivin receptors (both ActRIIA and B; and the Smad 2/3 pathway), toinhibit muscle protein synthesis and myocyte differentiation andproliferation. The absence of any of these ligands in developing animalsand humans results in a hypermuscular phenotype with an increased numberand size of muscle fibers. A postpartum reduction of myostatin levelsresults in the hypertrophy of skeletal muscle due to an increase in thesize of existing myofibers (Lee et al 2005; Lee et al 2010;Trendelenburg et al 2012). Thus, the capacity for modulating musclegrowth by perturbing this signaling pathway at the receptor level ismuch more substantial than previously appreciated by directanti-myostatin approaches.

“Myostatin antagonist” as used herein refers to a molecule capable ofantagonizing (e.g., reducing, inhibiting, decreasing, delaying)myostatin function, expression and/or signalling (e.g., by blocking thebinding of myostatin to the myostatin receptor, i.e., ActRIIB).Non-limiting examples of antagonists include myostatin binding moleculesand ActRII (ActRII A ActRIIB, or ActRIIA/B) receptor binding molecules.In some embodiments of the disclosed methods, regimens, kits, processes,uses and compositions, a myostatin antagonist is employed.

By “myostatin binding molecule” is meant any molecule capable of bindingto the human myostatin antigen either alone or associated with othermolecules. The binding reaction may be shown by standard methods(qualitative assays) including, for example, a binding assay,competition assay or a bioassay for determining the inhibition ofmyostatin binding to its receptor or any kind of binding assays, withreference to a negative control test in which an antibody of unrelatedspecificity, but ideally of the same isotype, e.g., an anti-CD25antibody, is used. Non-limiting examples of myostatin binding moleculesinclude small molecules, myostatin receptor decoys, and antibodies thatbind to myostatin as produced by B-cells or hybridomas and chimeric,CDR-grafted or human antibodies or any fragment thereof, e.g., F(ab′)₂and Fab fragments, as well as single chain or single domain antibodies.Preferably the myostatin binding molecule antagonizes (e.g., reduces,inhibits, decreases, delays) myostatin function, expression and/orsignalling. In some embodiments of the disclosed methods, regimens,kits, processes, uses and compositions, a myostatin binding molecule isemployed.

By “ActRII receptor inhibitor” is meant any molecule capable of bindingto the human ActRII receptor (ActRII A and/or ActRIIB) either alone orassociated with other molecules and inhibiting the receptor signalling.The binding and inhibiting reactions may be shown by standard methods(qualitative assays) including, for example, a binding assay,competition assay or a bioassay for determining the inhibition of ActRIIreceptor binding to myostatin or any kind of binding assays, withreference to a negative control test in which an antibody of unrelatedspecificity, but ideally of the same isotype, e.g., an anti-CD25antibody, is used. Non-limiting examples of ActRII receptor inhibitorsinclude small molecules, myostatin decoys, and antibodies to the ActRIIreceptor as produced by B-cells or hybridomas and chimeric, CDR-graftedor human antibodies or any fragment thereof, e.g., F(ab′)₂ and Fabfragments, as well as single chain or single domain antibodies.Preferably the ActRII receptor binding molecule antagonizes (e.g.,reduces, inhibits, decreases, delays) myostatin/activing function,expression and/or signalling. In some embodiments of the disclosedcombinations, uses, methods and compositions, an ActRII receptorinhibitor is employed.

Bimagrumab

Bimagrumab, the pharmaceutically active compound used in accordance withthe present invention, is a fully human, monoclonal antibody (modifiedIgG1, 234-235-Ala-Ala, λ2) developed to bind competitively to activinreceptor type II (ActRII) with greater affinity than its natural ligandsthat limit muscle mass growth, including myostatin and activin.Bimagrumab is cross-reactive with human and mouse ActRIIA and ActRIIBand effective on human, cynomolgus, mouse and rat skeletal muscle cells.Bimagrumab binds with extremely high affinity (KD 1.7±0.3 pM) to humanActRIIB and with relatively lower affinity to human ActRIIA (KD 434±25pM).

The present invention is based on the therapeutic approach thatsufficiently blocking myostatin binding to its receptor ActRII (ActRIIBand/or ActRIIA) will significantly reduce the activity of myostatin andother ligands that inhibit skeletal muscle growth acting at thereceptors, while allowing some of those ligands to perform their otherphysiologic functions via secondary receptors (Upton et al 2009). Otherapproaches to reducing myostatin activity, i.e. competitive solubleActRII, creating a soluble receptor sink may deplete a range of ActRIIligands with activities at other receptors, potentially creating agreater safety risk than using a receptor antagonist antibody likebimagrumab.

Other approaches include the use of or antibodies binding myostatin suchas LY2495655 (Eli Lilly), which will then inhibit or reduce signallingthrough the ActRII receptor.

As a potent inhibitor of ActRII, bimagrumab blocks the effects ofmyostatin, activin A, GDF11, and possibly other ligands working throughthis receptor.

The present invention therefore provides inter alia a myostatinantagonist or an activin (such as activin A, activin B or activin AB)antagonist preferably a myostatin binding molecule or antibody, and morepreferably an inhibitor or more preferably an anti-ActRII receptorantibody, most preferably bimagrumab, for use in the treatment of cancercachexia.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the present invention is described in detail withreference to accompanying figures in which:

FIG. 1: The effects of cisplatin and CDD866 on body weight (A, B, C),tumor volume (D) and weight (E) in CT-26 mouse colon cancer-inducedcachexia, either alone or in combination. Values are expressed asmeans±SEM (n=10). Percent changes of body weight were calculated incomparison to treatment start on day 0; *: P<0.05, **: P<0.01 versusNon-tumor control; ^(&&): P<0.01 versus CT-26 control; ⁺⁺: P<0.01 versusNon-tumor cisplatin; ^(##): P<0.01 versus CT-26 cisplatin by Sidak'smultiple comparison test following ANOVA.

FIG. 2 : The effects of cisplatin and CDD866 on muscle weight andtime-to-progression in CT-26 mouse colon cancer-induced cachexia, eitheralone or in combination. Values are expressed as means 35 SEM (n=10).Percent changes of muscle weight, normalized to initial body weight onday 0, were calculated in comparison to Non-tumor control (A, B, C); *:P<0.05, **: P<0.01 versus Non-tumor control; ^(&): P<0.05, ^(&&): P<0.01versus CT-26 control; ⁺⁺: P<0.01 versus Non-tumor cisplatin; ^(xx):P<0.01 versus Non-tumor CDD866; ^(##): P<0.01 versus CT-26 cisplatin;^($): P<0.05, ^($$): P<0.01 versus CT-26 CDD866 by Sidak's multiplecomparison test following ANOVA. Time-to-progression expressed by %event defined by interruption criteria (D); median days elapsed beforereaching an interruption criterion (E), expressed by box and whiskerswith min to max (n=10); ^(&): P<0.05, ^(&&): P<0.01 versus CT-26 control(Vehicle 1/Vehicle 2) by Dunn's multiple comparison test followingANOVA.

FIG. 3: The effects of everolimus and CDD866 on body weight (A, B, C),tumor volume (D) and weight (E) in CT-26 mouse colon cancer-inducedcachexia, either alone or in combination. Values are expressed asmeans±SEM (n=10). Percent changes of body weight were calculated incomparison to treatment start on day 0; *: P<0.05, **: P<0.01 versusNon-tumor control; ^(&&): P<0.01 versus CT-26 control; ⁺⁺: P<0.01 versusNon-tumor everolimus; ^(##): P<0.01 versus CT-26 everolimus by Sidak'smultiple comparison test following ANOVA.

FIG. 4: The effects of everolimus and CDD866 on muscle weight andtime-to-progression in CT-26 mouse colon cancer-induced cachexia, eitheralone or in combination. Values are expressed as means±SEM (n=10).Percent changes of muscle weight, normalized to initial body weight onday 0, were calculated in comparison to Non-tumor control (A, B, C); *:P<0.05, **: P<0.01 versus Non-tumor control; ^(&): P<0.05, ^(&&): P<0.01versus CT-26 control; ⁺⁺: P<0.01 versus Non-tumor everolimus; ^(xx):P<0.01 versus Non-tumor CDD866; ^(##): P<0.01 versus CT-26 everolimus;^($): P<0.05, ^($$): P<0.01 versus CT-26 CDD866 by Sidak's multiplecomparison test following ANOVA. Time-to-progression expressed by %event defined by interruption criteria (D); median days elapsed beforereaching an interruption criterion (E), expressed by box and whiskerswith min to max (n=10); ^(&): P<0.05, ^(&&): P<0.01 versus CT-26 control(Vehicle 1/Vehicle 2) by Dunn's multiple comparison test followingANOVA.

FIG. 5: mTOR is overexpressed in muscle of old vs young rats.

1. mTOR is overactive in skeletal muscle of old vs young rats.

2. mTOR is not appropriately down regulated after fasting in theskeletal muscle of old vs young rats.

DETAILED DESCRIPTION OF THE INVENTION

The present invention pertains to a combination comprising (a) anactivin receptor type II receptor inhibitor, and (b) a chemotherapeuticagent, or a pharmaceutically acceptable salt thereof, and uses thereof,for simultaneous, separate or sequential use for the treatment of cancercachexia in a subject.

It also pertains to the combination of (a) a moystatin or activinantagonist and (b) an mTOR inhibitor for treating age-relatedconditions.

The combination can be fixed or non-fixed, preferably non-fixed.

The general terms used herein are defined with the following meanings,unless explicitly stated otherwise:

The terms “comprising” and “including” are used herein in theiropen-ended and non-limiting sense unless otherwise noted.

The terms “a” and “an” and “the” and similar references in the contextof describing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

The term “combination” or “pharmaceutical combination” is defined hereinto refer to either a fixed combination in one dosage unit form, anon-fixed combination or a kit of parts for the combined administrationwhere an activin type II receptor (ActRID antagonist or blocker, and achemotherapeutic agent, or pharmaceutically acceptable salt thereof maybe administered independently at the same time or separately orsequentially within time intervals that allow that the combinationpartners show a cooperative, e.g., additive or synergistic, effect.

The term “fixed combination” means that the active ingredients ortherapeutic agents, are administered to a patient simultaneously in theform of a single entity or dosage form.

The term “non-fixed combination” means that the active ingredients ortherapeutic agents, are both administered to a patient as separateentities or dosage forms either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the three compounds in thebody of the subject, e.g., a mammal or human, in need thereof.

Preferably herein the term “combination” or “pharmaceutical combination”is a non-fixed combination.

The term “pharmaceutical composition” is defined herein to refer to amixture or solution containing at least one therapeutic agent to beadministered to a subject, e.g., a mammal or human, in order to treat aparticular disease or condition affecting the subject thereof.

The term “pharmaceutically acceptable” is defined herein to refer tothose compounds, biologic agents, materials, compositions and/or dosageforms, which are, within the scope of sound medical judgment, suitablefor contact with the tissues a subject, e.g., a mammal or human, withoutexcessive toxicity, irritation allergic response and other problemcomplications commensurate with a reasonable benefit/risk ratio.

The terms “combined administration” as used herein are defined toencompass the administration of the selected therapeutic agents to asingle subject, e.g., a mammal or human, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “treating” or “treatment” as used herein comprises a treatmentrelieving, reducing or alleviating at least one symptom in a subject oreffecting a delay of progression of a disease, condition and/ordisorder. For example, treatment can be the diminishment of one orseveral symptoms of a disorder or complete eradication of a disorder.Within the meaning of the present invention, the term “treat” alsodenotes to arrest, delay the onset (i.e., the period prior to clinicalmanifestation of a disease) and/or reduce the risk of developing orworsening a disease.

The term “progression-free survival” as used herein comprises the lengthof time during and after the treatment of a disease, such as cancer,that a patient lives with the disease but it does not get worse. In aclinical trial, measuring the progression-free survival is one way tosee how well a new treatment works. It is also called PFS.

The term “overall survival” as used herein comprises the length of timefrom either the date of diagnosis or the start of treatment for adisease, such as cancer, that patients diagnosed with the disease arestill alive. In a clinical trial, measuring the overall survival is oneway to see how well a new treatment works. It is also called OS.

The term “pharmaceutically effective amount” or “therapeuticallyeffective amount” of a combination of therapeutic agents is an amountsufficient to provide an observable improvement over the baselineclinically observable signs and symptoms of the disease.

The term “synergistic effect” as used herein refers to action of twoagents such as, for example, (a), and (b), or a pharmaceuticallyacceptable salt thereof, producing an effect, for example, promotingand/or enhancing an immune response in a subject, which is greater thanthe simple addition of the effects of each drug administered bythemselves. A synergistic effect can be calculated, for example, usingsuitable methods such as the Sigmoid-Emax equation (Holford, N. H. G.and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), theequation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp.Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation(Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Eachequation referred to above can be applied to experimental data togenerate a corresponding graph to aid in assessing the effects of thedrug combination. The corresponding graphs associated with the equationsreferred to above are the concentration-effect curve, isobologram curveand combination index curve, respectively.

The term “subject” or “patient” as used herein includes animals, whichare capable of promoting and/or enhancing an immune response and/orhaving an age related condition. Examples of subjects include mammals,e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice,rabbits, rats and transgenic non-human animals. In the preferredembodiment, the subject is a human, e.g., a human suffering from, atrisk of suffering from, or potentially capable of suffering from cancercachexia or an age related condition.

The term about” or “approximately” shall have the meaning of within 10%,more preferably within 5%, of a given value or range.

Herein after, the present invention is described in further detail andis exemplified.The present invention is provided in its following aspects:

-   -   1. A combination comprising (a) ActRII receptor inhibitor and b)        a chemotherapeutic agent.    -   2. A combination according to aspect 1 for simultaneous,        separate or sequential use.    -   3. A combination according to aspect 1 or 2, wherein the a)        ActRII receptor inhibitor, and b) a chemotherapeutic agent are        in separate form.    -   4. A combination according to aspects 1-3 wherein a) is an        anti-ActRII receptor antibody.    -   5. A combination according to aspects 1-4 wherein said        anti-ActRII antibody is bimagrumab    -   6. A combination according to aspects 1-5 wherein b) is a        platinum-containing anti-cancer agent.    -   7. A combination according to any of the preceding aspects for        use as a medicament.    -   8. A combination according to aspect 1-6 comprising (a) ActRII        receptor inhibitor and b) a chemotherapeutic agent for use in        the treatment of cancer cachexia.    -   9. A combination according for use according to aspects 1-6        wherein the treatment of cancer cachexia is reduction of body        weight loss.    -   10. An ActRII receptor inhibitor for use in treating cancer        cachexia.    -   11. An ActRII receptor inhibitor for use according to aspect 11,        wherein cancer cachexia is due to treatment with a        chemotherapeutic agent.    -   12. An ActRII receptor inhibitor for use according to any aspect        10-12, wherein the wherein treating cancer cachexia is reducing        body weight loss.    -   13. An ActRII receptor inhibitor for use according to aspects        10-12 in delaying time to progression of cancer in a patient.    -   14. An ActRII receptor inhibitor for use according to aspects        10-12 in delaying time to progression of cancer cachexia.    -   15. An ActRII receptor inhibitor for use according to aspects        10-12 in prolonging cancer survival.    -   16. An ActRII receptor inhibitor for use according to aspects        10-15, wherein the ActRII receptor inhibitor is an anti-ActRII        receptor antibody.    -   17. An ActRII receptor inhibitor for use according to aspect 16        wherein the anti-ActRII receptor antibody is bimagrumab    -   18. An ActRII receptor inhibitor for use according to aspects        11-17, wherein the chemotherapeutic agent is a        platinum-containing anti-cancer agent.    -   19. A combination comprising a) a myostatin antagonist and b) an        mTOR inhibitor.    -   20. A combination according to aspect 19 wherein the myostatin        antagonist is an ActRII receptor inhibitor    -   21. A combination according to aspect 20 wherein the ActRII        receptor inhibitor is an anti-ActRII receptor antibody.    -   22. A combination according to aspect 21 wherein the anti-ActRII        receptor antibody is bimagrumab.    -   23. A combination according to aspect 19-22 wherein the mTOR        inhibitor is everolimus.    -   24. A combination according to aspects 19-23 for use as a        medicament.    -   25. A combination according to aspects 19-23 for use in treating        cancer cachexia.    -   26. A combination according to aspects 19-23 wherein treating        cancer cachexia is preventing body weight loss.    -   27. A combination according to aspects 19-23 wherein treating        cancer cachexia is maintaining body weight.    -   28. A combination according to aspects 19-23 wherein treating        cancer cachexia is increasing body weight.    -   29. A combination according to aspects 1-9 or for use according        to aspects 19-28 wherein the agents are in separate        pharmaceutical compositions.    -   30. A combination according to any one of aspects 19-23 for use        in the treatment of an age related condition.    -   31. A combination of aspect 30, wherein the age related        condition is selected from the group consisting of sarcopenia,        skin atrophy, muscle wasting, brain atrophy, atherosclerosis,        arteriosclerosis, pulmonary emphysema, osteoporosis,        osteoarthritis, high blood pressure, erectile dysfunction,        dementia, Huntington's disease, Alzheimer's disease, cataracts,        age-related macular degeneration, prostate cancer, stroke,        diminished life expectancy, impaired kidney function, and        age-related hearing loss, aging-related mobility disability        (e.g., frailty), cognitive decline, age related dementia, memory        impairment, tendon stiffness, heart dysfunction such as cardiac        hypertrophy and systolic and diastolic dysfunction,        immunosenescence, cancer, obesity, and diabetes.    -   32. A myostatin antagonist for use in delaying time to        progression of cancer in a patient, wherein said patient is        treated with a chemotherapeutic agent.    -   33. A myostatin antagonist for use according to aspect 30,        wherein said chemotherapeutic agent is include        platinum-containing anti-cancer drugs such as cisplatin or        carboplatin, or a mTOR inhibitor such as everolimus.    -   34. A myostatin antagonist for use according to aspects 32-33        wherein said myostatin antagonist is an ActRII receptor        inhibitor.    -   35. A myostatin antagonist for use according to aspect 34        wherein said ActRII receptor inhibitor is an anti-ActRII        receptor antibody.    -   36. A myostatin antagonist for use according to aspect 35        wherein said anti-ActRII receptor antibody is bimagrumab.    -   37. A method of treating a subject having cancer cachexia which        comprises administering to said subject an ActRII receptor        inhibitor in quantity which is effective against said cancer        cachexia.    -   38. The method of aspect 37, wherein cancer cachexia is due to        treatment with a chemotherapeutic agent.    -   39. The method of aspect 38, wherein the chemotherapeutic agent        is a platinum-containing anti-cancer agent.    -   40. The method of any aspects 37-39, wherein treating cancer        cachexia is reducing body weight loss.    -   41. A method of delaying time to progression of cancer in a        subject having cancer which comprises administering to said        subject an ActRII receptor inhibitor in quantity which is        effective in delaying time to progression of cancer.    -   42. A method of delaying time to progression of cancer in a        subject having cancer cachexia which comprising administering to        said subject an ActRII receptor inhibitor in quantity which is        effective in delaying time to progression of cancer cachexia.    -   43. A method of prolonging cancer survival in a subject which        comprising administering to said subject an ActRII receptor        inhibitor in quantity which is effective in prolonging cancer        survival.    -   44. The method according to aspects 37-44, wherein the ActRII        receptor inhibitor is an anti-ActRII receptor antibody.    -   45. The method according to aspect 44, wherein the anti-ActRII        receptor antibody is bimagrumab.    -   46. A method of treating a subject having cancer cachexia which        comprises administering to said subject a myostatin antagonist        and an mTOR inhibitor.    -   47. A method of treating a subject having an age-related        condition which comprises administering to said subject a        myostatin antagonist and an mTOR inhibitor.    -   48. The method of aspects 46-47, wherein the myostatin        antagonist is an ActRII receptor inhibitor    -   49. The method according to aspect 48, wherein the ActRII        receptor inhibitor is an anti-ActRII receptor antibody.    -   50. The method according to aspect 49, wherein the anti-ActRII        receptor antibody is bimagrumab.    -   51. The method of aspects 46-50, wherein said mTOR inhibitor is        everolimus.    -   52. The method of aspects 46-50, wherein the age related        condition is selected from the group consisting of sarcopenia,        skin atrophy, muscle wasting, brain atrophy, atherosclerosis,        arteriosclerosis, pulmonary emphysema, osteoporosis,        osteoarthritis, high blood pressure, erectile dysfunction,        dementia, Huntington's disease, Alzheimer's disease, cataracts,        age-related macular degeneration, prostate cancer, stroke,        diminished life expectancy, impaired kidney function, and        age-related hearing loss, aging-related mobility disability        (e.g., frailty), cognitive decline, age related dementia, memory        impairment, tendon stiffness, heart dysfunction such as cardiac        hypertrophy and systolic and diastolic dysfunction,        immunosenescence, cancer, obesity, and diabetes.    -   53. A method of treatment according to any preceding use or        combination.

A preferred combination and uses thereof is bimagrumab and a platinumcontaining anti-cancer agent such as cisplatin.

Another preferred combination and uses thereof is bimagrumab and a mTORinhibitor such as everolimus.

Further aspects comprise:

A combination comprising a) ActRII receptor inhibitor such asbimagrumab, and b) a P13K inhibitor.

A combination according to any of the preceding aspects comprising anActRII receptor inhibitor such as bimagrumab and b) a VEGF receptorinhibitor.

A further specific aspect is a combination comprising a) ActRII receptorinhibitor such as bimagrumab, and b) a chemotherapeutic agent for use inimproving progression-free survival.

Another further specific aspect is a combination comprising a) ActRIIreceptor inhibitor such as bimagrumab, and b) a chemotherapeutic agentfor use in improving overall survival.

All aspects can be combined with each other within the scope of thepresent invention.

In further aspects, the invention provides pharmaceutical compositionsseparately comprising a quantity, which is jointly therapeuticallyeffective at treating cancer cachexia, uses thereof or methods oftreating cancer cachexia using such pharmaceutical compositions, fordelaying time to progression of cancer/cancer cachexia, for prolongingcancer survival, improving progression-free survival, or overallsurvival and for treating an age-related condition, of a combinationpartner (a) and a combination partner (b) which are administeredconcurrently but separately, or administered sequentially.

Bimagrumab

The manufacture of bimagrumab has been described in WO2010/125003.

Bimagrumab comprises an antigen binding site comprising at least oneimmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence hypervariable regions CDR1 of SEQ ID N° 1, CDR2 of SEQ ID N° 2and CDR3 of SEQ ID N° 3.

The use of antibodies having 1, 2 or 3 residues changed from any of thesequences of CDR1, CDR2 and/or CDR3 of the heavy chain is also comprisedwithin the scope of the invention.

Bimagrumab also comprises antigen binding site comprising at least oneimmunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1 of SEQ ID N° 4, CDR2 of SEQ ID N° 5and CDR3 of SEQ ID N° 6 or CDR equivalents thereof. The use ofantibodies having 1, 2 or 3 residues changed from any of the sequencesof CDR1, CDR2 and/or CDR3 of the light chain is also comprised withinthe scope of the invention.

Bimagrumab also comprises a light chain of SEQ ID N° 7 or SEQ ID N° 8and a heavy chain of SEQ ID N° 9.

According to the invention the use of antibodies having 95% identitywith the light chain and/or the heavy chain are also comprised.

SEQUENCE LISTING for BIMAGRUMAB  <130> PAT057144-US-PSP  <160> 9 <170> PatentIn version 3.5  <210> 1  <211> 10  <212> PRT <213> Artificial  <220>  <223> Heavy chain CDR1  <400> 1 Gly Tyr Thr Phe Thr Ser Ser Tyr Ile Asn  1          5           10 <210> 2  <211> 17  <212> PRT  <213> Artificial  <220> <223> Heavy chain CDR2  <400> 2 Thr Ile Asn Pro Val Ser Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1          5            10           15  Gly  <210> 3  <211> 6 <212> PRT  <213> Artificial  <220>  <223> Heavy chain CDR3  <400> 3 Gly Gly Trp Phe Asp Tyr  1          5  <210> 4  <211> 14  <212> PRT <213> Artificial  <220>  <223> Light chain CDR1  <400> 4 Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Tyr Val Asn 1          5           10  <210> 5  <211> 11  <212> PRT <213> Artificial  <220>  <223> Light chain CDR2  <400> 5 Leu Met Ile Tyr Gly Val Ser Lys Arg Pro Ser  1          5            10 <210> 6  <211> 10  <212> PRT  <213> Artificial  <220> <223> Light chain CDR3  <400> 6 Gly Thr Phe Ala Gly Gly Ser Tyr Tyr Gly  1         5            10 <210> 7  <211> 217  <212> PRT  <213> Artificial  <220> <223> light chain  <400> 7 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1          5           10           15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr         20            25            30 Asn Tyr Val Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu     35            40           45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe   50             55           60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65           70           75            80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Phe Ala Gly Gly           85           90           95 Ser Tyr Tyr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly        100           105            110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu      115            120          125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe   130           135           140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145           150            155            160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys           165           170           175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser         180           185           190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu      195           200           205 Lys Thr Val Ala Pro Thr Glu Cys Ser    210            215  <210> 8 <211> 217  <212> PRT  <213> Artificial  <220>  <223> light chain <400> 8 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1          5           10            15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr         20            25            30 Asn Tyr Val Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu     35            40            45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe    50           55           60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65           70           75            80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Phe Ala Gly Gly           85           90           95 Ser Tyr Tyr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly        100            105           110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu      115           120           125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe   130           135           140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145            150           155            160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys           165           170           175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser         180           185           190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu     195            200          205 Lys Thr Val Ala Pro Thr Glu Cys Ser    210            215  <210> 9 <211> 445  <212> PRT  <213> Artificial  <220>  <223> heavy chain <400> 9 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1         5            10            15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser        20            25           30 Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met      35             40           45 Gly Thr Ile Asn Pro Val Ser Gly Ser Thr Ser Tyr Ala Gln Lys Phe   50             55           60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65           70            75           80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys          85           90           95 Ala Arg Gly Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr        100           105           110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro      115           120           125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val   130           135           140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145          150           155           160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly          165            170          175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly        180           185           190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys      195            200          205 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys   210           215          220 Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu 225          230            235           240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu          245           250          255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys         260          265            270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys     275           280           285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu   290           295           300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305           310           315          320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys          325            330           335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser        340           345           350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys      355           360          365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln   370           375            380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385          390           395           400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln          405          410           415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn        420           425          430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys      435           440           445 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 305          310           315           320 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln          325             330            335 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met        340           345            350 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro      355          360           365 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn   370            375           380 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 385           390           395          400 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val           405           410          415 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln        420          425            430 Lys Ser Leu Ser Leu Ser Pro Gly Lys       435          440 

Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue,weakness, and significant loss of appetite in someone who is notactively trying to lose weight. The formal definition of cachexia is theloss of body mass (weight) that cannot be reversed nutritionally: evenif the affected patient eats more calories, lean body mass will be lost,indicating a primary pathology is in place.

Cachexia is seen in patients with cancer, AIDS chronic obstructive lungdisease, multiple sclerosis, congestive heart failure, tuberculosis,familial amyloid polyneuropathy, gadolinium poisoning, mercury poisoning(acrodynia) and hormonal deficiency.

It is a positive risk factor for death, meaning if the patient hascachexia, the chance of death from the underlying condition is increaseddramatically. It can be a sign of various underlying disorders; when apatient presents with cachexia, a doctor will generally consider thepossibility of cancer, metabolic acidosis (from decreased proteinsynthesis and increased protein catabolism), certain infectious diseases(e.g., tuberculosis, AIDS), chronic pancreatitis, and some autoimmunedisorders, or addiction to amphetamine. Cachexia physically weakenspatients to a state of immobility stemming from loss of appetite,asthenia, and anemia, and response to standard treatment is usuallypoor. Cachexia includes sarcopenia as a part of its pathology.

Cancer Cachexia:

Cancer cachexia is a multifactorial syndrome that is defined by anongoing loss of skeletal muscle mass (with or without loss of fat mass)that cannot be fully reversed by conventional nutritional support andthat leads to progressive functional impairment.

Chemotherapeutic Agents:

Chemotherapeutic agents include platinum-containing anti-cancer drugs(e.g. cisplatin, carboplatin), PI3K/mTOR inhibitor, everolimus, P13Kinhibitors and VEGFR inhibitors.

In a broader sense referring as “chemotherapy”, those include alkylatingagents (e.g. cyclophosphamide, temozolomide), platinum-containingagents, anti-metabolites (e.g. 5-fluorouracil, methotrexate,hydroxyurea, cytarabine, gemcitabine), topoisomerase inhibitor (e.g.doxorubicin, irinotecan), microtubule polymerizing/depolymerizing agent(e.g. vinblastine, vincristine, paclitaxel, docetaxel), endocrine agent(e.g. bicalutamide, leuprorelin, tamoxifen, letrozole), and morerecently molecular targeted agents (e.g. kinase inhibitors, antibodies).

mTOR Inhibitors:

As used herein, the term “mTOR inhibitor” refers to a compound orligand, or a pharmaceutically acceptable salt thereof, which inhibitsthe mTOR kinase in a cell. In an embodiment an mTOR inhibitor is anallosteric inhibitor. In an embodiment an mTOR inhibitor is a catalyticinhibitor.

Allosteric mTOR inhibitors include the neutral tricyclic compoundrapamycin (sirolimus), rapamycin-related compounds, that is compoundshaving structural and functional similarity to rapamycin including,e.g., rapamycin derivatives, rapamycin analogs (also referred to asrapalogs) and other macrolide compounds that inhibit mTOR activity.

Rapamycin is a known macrolide antibiotic produced by Streptomyceshygroscopicus having the structure shown in Formula A.

See, e.g., McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688;Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat.No. 3,929,992. There are various numbering schemes proposed forrapamycin. To avoid confusion, when specific rapamycin analogs are namedherein, the names are given with reference to rapamycin using thenumbering scheme of formula A.

Rapamycin analogs useful in the invention are, for example,O-substituted analogs in which the hydroxyl group on the cyclohexyl ringof rapamycin is replaced by OR₁ in which R₁ is hydroxyalkyl,hydroxyalkoxyalkyl, acylaminoalkyl, or aminoalkyl; e.g. RAD001, alsoknown as, everolimus as described in U.S. Pat. No. 5,665,772 andWO94/09010 the contents of which are incorporated by reference. Othersuitable rapamycin analogs include those substituted at the 26- or28-position. The rapamycin analog may be an epimer of an analogmentioned above, particularly an epimer of an analog substituted inposition 40, 28 or 26, and may optionally be further hydrogenated, e.g.as described in U.S. Pat. No. 6,015,815, WO95/14023 and WO99/15530 thecontents of which are incorporated by reference, e.g. ABT578 also knownas zotarolimus or a rapamycin analog described in U.S. Pat. No.7,091,213, WO98/02441 and WO01/14387 the contents of which areincorporated by reference, e.g. AP23573 also known as ridaforolimus.Examples of rapamycin analogs suitable for use in the present inventionfrom U.S. Pat. No. 5,665,772 include, but are not limited to,40-O-benzyl-rapamycin, 40-O-(4′-hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin,40-O-[3′-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′E,4′S)-40-O-(4′,5′-dihydroxypwent-2′-en-1-yl)-rapamycin,40-O-(2-hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(2-hydroxy)ethyl-rapamycin , 40-O-(3-hydroMpropyl-rapamycin,40-O-(6-hydroxy)hexyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-dihydroxyprop-1-yl]-rapamycin,40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-morpholino)acetoxy]ethyl-rapamycin,40-O-(2-N-imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin,40-O-(2-aminoethyl)-rapamycin, 40-O-2-acetaminoethyl)-rapamycin,40-O-(2-nicotinamidoethyl)-rapamycin,40-O-(2-(N-methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-tolylsulfonamidoethyl)-rapamycin and40-O-[2-(4′,5′-dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin.

Other rapamycin analogs useful in the present invention are analogswhere the hydroxyl group on the cyclohexyl ring of rapamycin and/or thehydroxy group at the 28 position is replaced with an hydroxyester groupare known, for example, rapamycin analogs found in U.S. RE44,768, e.g.temsirolimus.

Other rapamycin analogs useful in the present invention include thosewherein the methoxy group at the 16 position is replaced with anothersubstituent, preferably (optionally hydroxy-substituted) alkynyloxy,benzyl, orthomethoxybenzyl or chlorobenzyl and/or wherein the mexthoxygroup at the 39 position is deleted together with the 39 carbon so thatthe cyclohexyl ring of rapamycin becomes a cyclopentyl ring lacking the39 position methyoxy group; e.g. as described in WO95/16691 andWO96/41807 the contents of which are incorporated by reference. Theanalogs can be further modified such that the hydroxy at the 40-positionof rapamycin is alkylated and/or the 32-carbonyl is reduced.

Rapamycin analogs from WO95/16691 include, but are not limited to,16-demthoxy-16-(pent-2-ynyl)oxy-rapamycin,16-demthoxy-16-(but-2-ynyl)oxy-rapamycin,16-demthoxy-16-(propargyl)oxy-rapamycin,16-demethoxy-16-(4-hydroxy-but-2-ynyl)oxy-rapamycin,16-demthoxy-16-benzyloxy-40-O-(2-hyd roxyethyl)-rapamycin,16-demthoxy-16-benzyloxy-rapamycin,16-demethoxy-16-ortho-methoxybenzyl-rapamycin,16-demethoxy-40-O-(2-methoxyethyl)-16-pent-2-ynyl)oxy-rapamycin,39-demethoxy-40-desoxy-39-formyl-42-nor-rapamycin,39-demethoxy-40-desoxy-39-hydroxymethyl-42-nor-rapamycin,39-demethoxy-40-desoxy-39-carboxy-42-nor-rapamycin,39-demethoxy-40-desoxy-39-(4-methyl-piperazin-1-yl)carbonyl-42-nor-rapamycin,39-demethoxy-40-desoxy-39-(morpholin-4-yl)carbonyl-42-nor-rapamycin,39-demethoxy-40-desoxy-39-[N-methyl,N-(2-pyridin-2-yl-ethyl)]carbamoyl-42-nor-rapamycin and39-demethoxy-40-desoxy-39-(p-toluenesulfonylhydrazonomethyl)-42-nor-rapamycin.

Rapamycin analogs from WO96/41807 include, but are not limited to,32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo-rapamycin,16-O-pent-2-ynyl-32-deoxo-40-O-(2-hydroxy-ethyl)-rapamycin,16-O-pent-2-ynyl-32-(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin,32(S)-dihydro-40-O-(2-methoxy)ethyl-rapamycin and32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin.

Another suitable rapamycin analog is umirolimus as described inUS2005/0101624 the contents of which are incorporated by reference.

In mammalian cells, the target of rapamycin (mTOR) kinase exists as amultiprotein complex described as the mTORC1 complex or mTORC2 complex,which senses the availability of nutrients and energy and integratesinputs from growth factors and stress signaling. The mTORC1 complex issensitive to allosteric mTOR inhibitors such as rapamycin, is composedof mTOR, GβL, and regulatory associated proteins of mTOR (raptor), andbinds to the peptidyl-prolyl isomerase FKBP12 protein (a FK506-bindingprotein 1A, 12 kDa). In contrast, the mTORC2 complex is composed ofmTOR, GβL, and rapamycin-insensitive companion proteins of mTOR(rictor), and does not bind to the FKBP12 protein in vitro.

The mTORC1 complex has been shown to be involved in proteintranslational control, operating as a growth factor and nutrientsensitive apparatus for growth and proliferation regulation. mTORC1regulates protein translation via two key downstream substrates: P70 S6kinase, which in turn phosphorylates ribosomal protein P70 S6, andeukaryotic translation initiation factor 4E binding protein 1 (4EBP1),which plays a key role in modulating elF4E regulated cap-dependenttranslation. The mTORC1 complex regulates cell growth in response to theenergy and nutrient homeostasis of the cell, and the deregulation ofmTORC1 is common in a wide variety of human cancers. The function ofmTORC2 involves the regulation of cell survival via phosphorylation ofAkt and the modulation of actin cytoskeleton dynamics.

The mTORC1 complex is sensitive to allosteric mTOR inhibitors such asrapamycin and derivatives in large part due to rapamycin's mode ofaction, which involves the formation of an intracellular complex withthe FKBP12 and binding to the FKBP12-rapamycin binding (FRB) domain ofmTOR. This results in a conformational change in mTORC1 which isbelieved to alter and weaken the interaction with its scaffoldingprotein raptor, in turn impeding substrates such as P70 S6K1 fromaccessing mTOR and being phosphorylated. Rapamycin and rapalogues suchas RAD001 have gained clinical relevance by inhibiting hyperactivationof mTOR associated with both benign and malignant proliferationdisorders. RAD001, otherwise known as everolimus (Afinitor®), has thechemical name(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaoneand the followina chemical structure

Everolimus is an FDA approved drug for the treatment of advanced kidneycancer and is being investigated in several other phase III clinicaltrials in oncology. Preclinical studies have shown that Everolimus isable to inhibit the proliferation of a wide variety of tumor cell linesboth in vitro and in vivo, presumably through the suppression ofrapamycin sensitive mTORC1 function. Everolimus, as a derivative ofrapamycin, is an allosteric mTOR inhibitor that is highly potent atinhibiting part of the mTORC1 function, namely P70 S6 kinase (P70 S6K)and the downstream P70 S6K substrate P70 S6. Allosteric mTOR inhibitorslike everolimus (and other rapamycin analogs) have little or no effectat inhibiting the mTORC2 pathway, or its resulting activation of Aktsignaling. Further examples of allosteric mTOR inhibitors includesirolimus (rapamycin, AY-22989),40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (alsocalled temsirolimus or CCI-779) and ridaforolimus (AP-23573/MK-8669).Other examples of allosteric mTOR inhibtors include zotarolimus (ABT578)and umirolimus.

Alternatively or additionally, catalytic, ATP-competitive mTORinhibitors have been found to target the mTOR kinase domain directly andtarget both mTORC1 and mTORC2. These are also more complete inhibitorsof mTORC1 than such allosteric mTOR inhibitors as rapamycin, becausethey modulate rapamycin-resistant mTORC1 outputs such as 4EBP1-T37/46phosphorylation and cap-dependent translation.

The combination of bimagrumab and mTOR inhibitors such as everolimus maybe particularly effective for the treatment of aging-related muscledysfunction because bimagrumab increases muscle mass and everolimusimproves muscle quality. Bimagrumab improves muscle mass by inhibitingthe myostatin/activin pathway. Everolimus improves muscle function byinhibiting the mTOR pathway which is over-active in old muscle(unpublished internal data that we could add). Inhibition of mTOR mayimprove muscle function by enhancing mitochondrial function, decreasinginflammation and increasing autophagy. Improving muscle mass andfunction with the combination of bimagrumab and mTOR inhibitors such aseverolimus is likely to have therapeutic benefit in sarcopenia and heartfailure. In addition, improving muscle mass and function may havetherapeutic benefit in diabetes mellitus by increasing glucose uptake inmuscle. Increased mTOR activity has also been demonstrated in musclebiopsies obtained from older healthy subjects (ages 60-84) as comparedto younger healthy subjects (ages 18-40) (Markofski M et al., ExpGeront, 2015)

EXAMPLES

Hereinafter, the present invention is described in more details andspecifically with reference to the examples, which however are notintended to limit the present invention.

Material and Methods

Materials

Bimagrumab is a human, IgG1 Leu234Ala/Leu235Ala monoclonal antibodydirected against ActRII. CDD866, a murinized version of bimagrumab,where the human Fc region of the antibody has been replaced by a mouseFc.CDD866 was produced in CHO cells at Novartis Pharma AG (Basel,Switzerland). Cisplatin (cis-diamminedichloro-platinum(II)) waspurchased from Sigma Aldrich (catalog number 479306). Everolimus wassynthesized at Novartis Pharma AG.

Animal Experiments

Adult male Balb/cJRj mice at the age of 11 to 12 weeks were purchasedfrom Janvier Laboratories (Le Genest St Isle, France). Mice wereacclimated to the facility for 7 days. Animals were housed in groups of5 or less animals at 25° C. with a 12:12 h light-dark cycle. They werefed a standard laboratory diet containing 18.2% protein and 3.0% fatwith an energy content of 15.8 MJ/kg (NAFAG 3890, Kliba, Basel,Switzerland). Food and water were provided ad libitum.

Mouse colon cancer cell line CT-26 was cultured in RPMI 1640 mediumsupplemented with 10% heat inactivated fetal bovine serum andantibiotic-antimycotic solution at 37° C. with 5% CO₂. CT-26 cells wereharvested by treatment with Accutase® (PAA Laboratories GmbH, Pasching,Austria) and suspended in a solution containing 50% PBS and 50% BDMatrigel™ Matrix without phenol red (catalog number 356237, BDBiosciences, Bedford, Mass., USA). A 0.1 mL of cell suspensioncontaining 3×10⁵ cells was inoculated subcutaneously into the left flankof mice. When tumors were palpable, mice bearing tumors with acceptablemorphology and size were randomized to produce groups balanced withrespect to mean and range of tumor sizes and body weight. Treatmentswere initiated on the day of randomization. Therapeutic interventionstudy was conducted to evaluate the effect of CDD866, either alone or incombination with anti-cancer agents. CDD866 was administered at 20 mg/kgs.c., once or twice weekly in a volume of 5 mL/kg. Cisplatin wasadministered at 1 mg/kg i.p. twice a week. Everolimus was administeredat 5 mg/kg p.o. once daily. In the combination groups, cisplatin oreverolimus treatment was combined with once or twice weekly subcutaneoustreatment of CDD866, respectively. Body weight and tumor volume weremeasured 2 to 3 times per week. At the end of the experiment, the micewere euthanized with CO₂, and tumor, tibialis anterior,gastrocnemius-soleus-plantaris complex, quadriceps were collected andweighed.

Time-to-progression study was performed as a follow-up to assess if thecombination of CDD866 and cisplatin or everolimus slows progression ofcancer cachexia to the interruption criteria which was defined by bodyweight loss reaching to 20% or tumor volume exceeding 1,500 mm³. Thetreatment regimen was the same as used in the therapeutic interventionstudy. Body weight and tumor volume were measured 2 to 3 times per weekin the first 2 weeks and then every day until the end of experiment. Themice were euthanized with CO₂, when body weight loss was close to 20% ortumor volume exceeded 1,500 mm³.

Protein Analysis

Lysis buffer consisting of extraction reagent (Phosphosafe; NovagenInc., Madison, Wis., USA) supplemented with 1% protease inhibitorcocktail (calbiochem #539131) and 0.2% SDS was added. PrecellysHomogenates (FastPrep-Machine FP20), were separated by centrifugationfor 20 minutes at 4° C. (14,000 rpm). Supernatants were collected andprotein contents measured a commercial kit for protein determination(BCA Kit; Thermo Scientific). Samples were diluted in SDS-PAGE samplebuffer and denatured for 10 minutes at 70° C. Equal amounts of proteinwere loaded per lane of 4 to 12% and 8% polyacrylamide gel (NuPAGEBis-Tris gel; Invitrogen Corp., Carlsbad, Calif., USA), separated byelectrophoresis, and then transferred onto nitrocellulose membranes.Membranes were blocked in TBS with 0.1% Tween and 5% w/v non-fat milkpowder. Primary antibodies phospho-SMAD3 (Millipore #04 1042 diluted1:1000) and α-Tubulin (Sigma T6199 Diluted 1:5000) were incubated in TBSwith 0.1% Tween 20 and 5% w/v non-fat milk powder and secondaryantibodies in TBS with 0.1% Tween 20, 0.05% SDS and 5% non-fat milk.Immunoreactivity was detected by SuperSignal West Femto MaximumSensitivity Substrate (Thermo Scientific) and exposed to film oracquired by FusionSpectra. Quantitative determination of mTOR and IL-6was performed using an assay kit from MesoScale Discovery using aMesoScale Discovery reader according to the manufacturers instruction.

Statistical Analysis

Values are expressed as mean±SEM. Statistical analysis was carried outusing Sidak's multiple comparison test following analysis of variance tocompare the treatment groups to the control groups (non-tumor andtumor-bearing), anti-cancer agent alone (cisplatin or everolimus) orCDD866 alone in the therapeutic intervention study, and Dunn's multiplecomparisons test for time-to-progression study. Differences wereconsidered to be significant when the probability value was <0.05.Statistical analyses were performed by GraphPad Prism (GraphPadSoftware, Inc., La Jolla, Calif., USA). Body weight was expressed as %change from day 0 as the start of treatment. Tumor volumes in cubic mmwere calculated according to the formula (length×width²)/2. Muscleweight was normalized to the body weight on the day of cell inoculation(initial body weight) and then expressed as % change from the non-tumorcontrol group.

Example 1 Bimagrumab Prevents Cisplatin-Induced Body Weight Loss

Extensive body weight loss has emerged as a key determinant ofcancer-related death. Thus longitudinally body weight development wasmonitored (FIGS. 1A and B). Ten days after starting the treatment,tumor-bearing animals receiving cisplatin as a mono-therapy had lost 20%of their initial body weight (FIGS. 1B and C). By contrast,vehicle-treated, tumor-bearing animals experienced a body weightdecrease of 10%, while animals treated with CDD866 alone or incombination with cisplatin exhibited moderate body weight losses of only3 and 5%, respectively (FIGS. 1B and C). In healthy control animals,cisplatin did not affect body weight and CDD866 administration resultedin a marked body weight gain in the absence and presence of cisplatin(FIGS. 1A and C). These data demonstrate that cisplatin, at an effectiveanti-tumor dose (cf. FIG. 1E), indeed precipitated body weight loss incachectic animals and that CDD866 significantly reducedchemotherapy-induced wasting.

Major concerns to be addressed in this study were potential drug-druginteractions that might reduce the efficacy of chemotherapy and impactsof CDD866 on tumor growth promotion. At treatment initiation, theaverage tumor volume was 260 mm³ (FIG. 1D). CDD866 neither acceleratedtumor progression (FIGS. 1D and E), nor did it impair the anti-tumoreffect of cisplatin (FIGS. 1D and E). Thus, CDD866 is efficacious inreducing chemotherapy-mediated body weight loss in cancer cachexiawithout interfering with the anti-tumor effect of cisplatin.

Example 2 Bimagrumab Antagonizes Cisplatin-Induced Muscle Wasting

Given the positive effect of CDD866 on body weight, we next determinedthe impact of the various interventions on individual skeletal muscles.In gastrocnemius, cisplatin provoked a muscle weight loss of 25%. CDD866treatment tended to reduce muscle weight loss to 13% and this protectiveeffect was preserved in the presence of cisplatin (12%) (FIG. 2B). Asimilar level of protection was observed in quadriceps muscle (FIG. 2C).Tibialis anterior benefited most from CDD866 treatment. In tibialisanterior, cisplatin-treated animals experienced a muscle wasting of 34%and co-administration of CDD866 reduced muscle loss significantly to 16%(FIG. 2A).

Example 3 Bimagrumab in Combination with Cisplatin Delays Time toProgression in Cancer Cachexia

Extensive tumor growth and subsequent body weight loss are importantpredictors of mortality in cancer patients. We therefore wanted toevaluate whether the combination of CDD866 and cisplatin has an impacton the length of survival. For ethical reason we abstained fromclassical survival studies. Instead, each mouse was individuallyeuthanized when experiencing either a body weight loss exceeding 20% ofinitial body weight, or reaching a tumor volume of 1,500 mm³, determinedas time-to-progression.

On average, animals receiving vehicle or cisplatin had to be sacrificedafter 12 and 12 days, respectively (FIGS. 2D and E). CDD866 treatedanimals had to be euthanized after 16 days, which corroborates previousfindings that CDD866 treatment reduced body weight loss, but did notpromote tumor growth. The combined treatment of CDD866 and cisplatin wassuperior to any other intervention tested. Indeed, combination treatmentextended time-to-progression up to 21 days (FIG. 2E). Monitoring wasstopped after 39 days with 35% of animals in the combination group stillnot having reached one of the defined interruption criteria (FIG. 2D).

Combination with Cisplatin

Despite substantial tumor growth inhibition, cisplatin accelerated bodyweight loss in cachectic animals, likely due to the high toxicity of theanti-cancer agent. CDD866 fully prevented cisplatin-mediated body weightloss demonstrating that ActRII inhibition remained efficacious in thepresence of cisplatin. Cisplatin treatment alone and also in combinationwith CDD866 reduced CT-26 tumor weight to similar levels, whichunderlines that the anti-cancer effect of cisplatin was not negativelyaffected by CDD866.

Consistently, cisplatin treatment did not improve CT-26 tumor-inducedskeletal muscle wasting, but rather tended to exacerbate skeletal muscleloss. In contrast, administration of CDD866 alone or in combination withcisplatin protected from skeletal muscle weight loss compared to animalsreceiving only cisplatin, corroborating further that ActRII inhibitionremains fully efficacious under cisplatin treatment. These results thusdemonstrate that CDD866 in combination with cisplatin counters musclewasting in cachectic animals when compared to cisplatin treatment alone.Noteworthy, CDD866 was administered only once per week and mice receivedonly two injections throughout the entire study (apart from the survivalstudies). Since the release of Activin by cancer tissues¹⁷ mightpotentially compete with ActRII inhibition by CDD866, a higher dosing orfrequency of dosing of CDD866 might be required in cancer cachexia toelicit more pronounced or maximal responses. Indeed, stronger musclewasting sparing was noticed with CDD866 alone in the combination studywith everolimus under a more frequent dosing regimen.

Cancer patients with low muscle mass are at increased risk fortreatment-related toxicities from chemotherapy and show increasedoverall mortality¹⁸. Consistently, CDD866 significantly delayed diseaseprogression largely by increasing muscle mass. Time-to-progression incancer cachexia was even further retarded by concomitant therapy withCDD866 and cisplatin, which simultaneously countered muscle wasting andinhibited tumor growth

Example 4 Bimagrumab and Everolimus Prevent Cancer Cachexia in anAdditive Way

In the next step, everolimus, a molecular-targeted agent againstmammalian Target of Rapamycin (mTOR), was selected as a combinationpartner because mTOR is known to play a pivotal role in cell growth andproliferation. In addition, treatment frequency for CDD866 was increasedto twice weekly to ensure significant anti-cachectic effect whenadministered as single agent, and the combination of everolimus andCDD866 was evaluated in non-tumor mice as well as tumor-bearingcachectic mice.

In the non-tumor bearing group, body weight gain was not affectedsignificantly by everolimus treatment. In contrast, body weight gainincreased significantly with CDD866 treatment as expected (FIG. 3A andC). The body weight increase was slightly slower in the combinationgroup (FIG. 3A and C), but still significantly different from everolimusalone, and not significantly different from CDD866 alone up to thetermination on day 14. In the CT-26 group, body weight was significantlydecreased in the tumor-bearing control group on day 14 when compared tothe non-tumor control group (FIGS. 3B and C). CT-26-induced loss in bodyweight was completely prevented by everolimus, CDD866 and thecombination of everolimus and CDD866. The effect of CDD866 on bodyweight was maintained in the presence of everolimus.

Everolimus slowed CT-26 tumor growth, and the anti-tumor effect wasmaintained in the presence of CDD866 (FIG. 3D). CT-26 tumor weight wassignificantly reduced with everolimus treatment alone or in combinationwith CDD866. There was no significant effect of CDD866 treatment onCT-26 tumor weight.

In the non-tumor bearing group, the weight of tibialis anterior,gastrocnemius-soleus-plantaris complex and quadriceps muscles was notaffected by everolimus treatment and significantly increased by CDD866treatment (FIG. 4A-C). The effect of CDD866 on muscle weight wasmaintained in the presence of everolimus. CT-26 tumor induced asignificant decrease in the weight of tibialis anterior,gastrocnemius-soleus-plantaris complex and quadriceps muscles comparedto the non-tumor bearing control group (FIG. 4A-C). CT-26-induced muscleweight loss was significantly reduced by everolimus or CDD866 treatment.Interestingly the combination of everolimus and CDD866 appeared toreverse skeletal muscle weight loss in an additive way, and the effectof the combined treatment was significantly different from theeverolimus treatment alone.

Example 5 Bimagrumab in Combination with Everolimus Delays Time toProgression in Cancer Cachexia

In addition to the beneficial effects of everolimus and CDD866 onCT-26-induced cachexia in the therapeutic intervention study, the effectof these treatments on progression of cancer and the associated cachexiawas evaluated, using the same criteria as used in the cisplatincombination study. In the CT-26 control group, the median days elapseduntil an interruption criterion (time-to-progression) was 17.5 daysafter randomization and treatment start (FIGS. 4D and E). Everolimustreatment significantly prolonged time-to-progression to 23 days mainlydue to its anti-tumor effect, while CDD866 showed only a non-significanttrend of extension to 21 days. The lack of significance of CDD866 ontime-to-progression is explained by the fact that, although thetreatment was highly successful in preventing body weight loss, it didnot inhibit tumor growth, which was the 2^(nd) interruption criterion.Importantly, the combination of everolimus and CDD866 appeared tofurther slow time-to-progression to 28.5 days, an effect which wassignificant compared to the CT-26 control group.

Combination with Everolimus

Since mTOR is known to play a pivotal role in cell growth andproliferation, mTOR inhibition by everolimus exhibited significantanti-tumor effect as expected, both in the absence and presence ofCDD866. This result clearly shows that anti-cancer effect of everolimusis not affected negatively by ActRII inhibition with CDD866. In linewith body weight decreases caused by CT-26 tumor, skeletal muscle weightwas significantly decreased in the CT-26 control group. Everolimus orCDD866 treatment alone significantly protected the tumor-bearing miceagainst skeletal muscle weight loss caused by CT-26 tumor.Interestingly, ActRII inhibition by CDD866 not only remains efficaciousin the presence of everolimus but also showed a non-significant trendfor an additive effect on reversing skeletal muscle weight loss, despitethe fact that mTOR is required for normal muscle growth. Similarly, inthe non-tumor-bearing mice, there was no effect on body weight byeverolimus treatment, while CDD866 increased body weight significantly.The effect of CDD866 on body weight was maintained in the presence ofeverolimus, clearly showing that the mTOR inhibition did not alter theeffect of CDD866 on body weight. Also the muscle anabolic responseobserved upon CDD866 treatment in non-tumor bearing mice was significantand not affected by mTOR inhibition at dose clearly effective on tumor.

Everolimus treatment alone prolonged time-to-progression as a surrogatefor survival and also CDD866 showed a trend of extension. Importantly,the combination of everolimus and CDD866 appeared to further slow-downtime-to-progression. Each treatment worked complementary to exert thebeneficial effect, with everolimus inhibiting tumor growth and CDD866preventing cachexia. A trend for an additive anti-cachectic effectobserved in the combination of CDD866 and everolimus needs furtherexploration on how ActRII blockade and mTOR inhibition interactspositively on skeletal muscle undergoing cachexia.

It is reported that mTORC1 is activated denervation-induced skeletalmuscle atrophy, but anti-atrophy effect of mTOR inhibition by rapamycintreatment was inconclusive. Activation of mTOR is also reported in otherpathological conditions, such as aging, obesity, insulin resistance anddiabetes, where mTOR inhibition seems to be beneficial. In the presentstudy, there was a significant increase in phosphorylation as well astotal amount of mTOR in the tumor-bearing mice. Therefore, it could bethat such aberrant activation of mTOR in CT-26 colon cancer-inducedcachexia also contributes to cachexia caused by cells, and thereforemTOR inhibition showed an additional benefit when combined with ActRIIblockade.

Example 6 Combination of an mTOR Inhibitor and a Myostatin Antagonist inAgeing

The combination of bimagrumab and mTOR inhibitors such as everolimus maybe particularly effective for the treatment of aging-related muscledysfunction because bimagrumab increases muscle mass and everolimusimproves muscle quality. Bimagrumab improves muscle mass by inhibitingthe myostatin/activin pathway. Everolimus improves muscle function byinhibiting the mTOR pathway which is over-active in old muscle.Inhibition of mTOR may improve muscle function by enhancingmitochondrial function, decreasing inflammation and increasingautophagy. Improving muscle mass and function with the combination ofbimagrumab and mTOR inhibitors such as everolimus is likely to havetherapeutic benefit in sarcopenia and heart failure. In addition,improving muscle mass and function may have therapeutic benefit indiabetes mellitus by increasing glucose uptake in muscle.

The data in FIG. 5 supports the rationale for the beneficial use of anmTOR inhibitors and a myostatin/activin pathway antagonist (e.g.,bimagrumab) in aging, and shows that:

1. mTOR is overactive in skeletal muscle of old vs young rats

2. mTOR is not appropriately down regulated after fasting in theskeletal muscle of old vs young rats.

REFERENCES

The entire content of the following references, in particularly theirdefinitions and descriptions in relation to, are incorporated herein byreference.

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1. A combination comprising (a) ActRII receptor inhibitor and b) achemotherapeutic agent.
 2. A combination according to claim 1 forsimultaneous, separate or sequential use.
 3. A combination according toclaim 1 or 2, wherein the a) ActRII receptor inhibitor, and b) achemotherapeutic agent are in separate form.
 4. A combination accordingto claim 1-3 wherein a) is an anti-ActRII receptor antibody.
 5. Acombination according to claims 1-4 wherein said anti-ActRII antibody isbimagrumab
 6. A combination according to claims 1-5 wherein b) is aplatinum-containing anti-cancer agent.
 7. A combination according to anyof the preceding claims for use as a medicament.
 8. A combinationaccording to claim 1-6 comprising (a) ActRII receptor inhibitor and b) achemotherapeutic agent for use in the treatment of cancer cachexia.
 9. Acombination according for use according to claim 8 wherein the treatmentof cancer cachexia is reduction of body weight loss.
 10. An ActRIIreceptor inhibitor for use in treating cancer cachexia.
 11. An ActRIIreceptor inhibitor for use according to claim 10, wherein cancercachexia is due to treatment with a chemotherapeutic agent.
 12. AnActRII receptor inhibitor for use according to any claim 10-11, whereinthe wherein treating cancer cachexia is reducing body weight loss. 13.An ActRII receptor inhibitor for use according to claims 10-12 indelaying time to progression of cancer in a patient.
 14. An ActRIIreceptor inhibitor for use according to claims 10-12 in delaying time toprogression of cancer cachexia.
 15. An ActRII receptor inhibitor for useaccording to claims 10-12 in prolonging cancer survival.
 16. An ActRIIreceptor inhibitor for use according to claims 10-15, wherein the ActRIIreceptor inhibitor is an anti-ActRII receptor antibody.
 17. An ActRIIreceptor inhibitor for use according to claim 16 wherein the anti-ActRIIreceptor antibody is bimagrumab
 18. An ActRII receptor inhibitor for useaccording to claims 11-17, wherein the chemotherapeutic agent is aplatinum-containing anti-cancer agent.
 19. A combination comprising a) amyostatin antagonist and b) an mTOR inhibitor.
 20. A combinationaccording to claim 19 wherein the myostatin antagonist is an ActRIIreceptor inhibitor
 21. A combination according to claim 20 wherein theActRII receptor inhibitor is an anti-ActRII receptor antibody.
 22. Acombination according to claim 21 wherein the anti-ActRII receptorantibody is bimagrumab.
 23. A combination according to claim 19-22wherein the mTOR inhibitor is everolimus.
 24. A combination according toclaims 19-23 for use as a medicament.
 25. A combination according toclaims 19-23 for use in treating cancer cachexia.
 26. A combinationaccording to claims 19-23 wherein treating cancer cachexia is preventingbody weight loss.
 27. A combination according to claims 19-23 whereintreating cancer cachexia is maintaining body weight.
 28. A combinationaccording to claims 19-23 wherein treating cancer cachexia is increasingbody weight.
 29. A combination according to claims 1-9 or for useaccording to claims 19-28 wherein the agents are in separatepharmaceutical compositions.
 30. A combination according to any one ofclaims 19-23 for use in the treatment of an age related condition.
 31. Acombination of claim 30, wherein the age related condition is selectedfrom the group consisting of sarcopenia, skin atrophy, muscle wasting,brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema,osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction,dementia, Huntington's disease, Alzheimer's disease, cataracts,age-related macular degeneration, prostate cancer, stroke, diminishedlife expectancy, impaired kidney function, and age-related hearing loss,aging-related mobility disability (e.g., frailty), cognitive decline,age related dementia, memory impairment, tendon stiffness, heartdysfunction such as cardiac hypertrophy and systolic and diastolicdysfunction, immunosenescence, cancer, obesity, and diabetes.
 32. Amyostatin antagonist for use in improving progression-free survival in acancer patient, wherein said patient is treated with a chemotherapeuticagent.
 33. A myostatin antagonist for use according to claim 32, whereinsaid chemotherapeutic agent is include platinum-containing anti-cancerdrugs such as cisplatin or carboplatin, or a mTOR inhibitor such aseverolimus.
 34. A myostatin antagonist for use according to claims 32-33wherein said myostatin antagonist is an ActRII receptor inhibitor.
 35. Amyostatin antagonist for use according to claim 34 wherein said ActRIIreceptor inhibitor is an anti-ActRII receptor antibody.
 36. A myostatinantagonist for use according to claim 35 wherein said anti-ActRIIreceptor antibody is bimagrumab.
 37. A method of treating a subjecthaving cancer cachexia which comprises administering to said subject anActRII receptor inhibitor in quantity which is effective against saidcancer cachexia.
 38. The method of claim 37, wherein cancer cachexia isdue to treatment with a chemotherapeutic agent.
 39. The method of claim38, wherein the chemotherapeutic agent is a platinum-containinganti-cancer agent.
 40. The method of any claims 37-39, wherein treatingcancer cachexia is reducing body weight loss.
 41. A method of delayingtime to progression of cancer in a subject having cancer which comprisesadministering to said subject an ActRII receptor inhibitor in quantitywhich is effective in delaying time to progression of cancer.
 42. Amethod of delaying time to progression of cancer in a subject havingcancer cachexia which comprising administering to said subject an ActRIIreceptor inhibitor in quantity which is effective in delaying time toprogression of cancer cachexia.
 43. A method of prolonging cancersurvival in a subject which comprising administering to said subject anActRII receptor inhibitor in quantity which is effective in prolongingcancer survival.
 44. The method according to claims 37-44, wherein theActRII receptor inhibitor is an anti-ActRII receptor antibody.
 45. Themethod according to claim 44, wherein the anti-ActRII receptor antibodyis bimagrumab.
 46. A method of treating a subject having cancer cachexiawhich comprises administering to said subject a myostatin antagonist andan mTOR inhibitor.
 47. A method of treating a subject having anage-related condition which comprises administering to said subject amyostatin antagonist and an mTOR inhibitor.
 48. The method of claims46-47, wherein the myostatin antagonist is an ActRII receptor inhibitor49. The method according to claim 48, wherein the ActRII receptorinhibitor is an anti-ActRII receptor antibody.
 50. The method accordingto claim 49, wherein the anti-ActRII receptor antibody is bimagrumab.51. The method of claims 46-50, wherein said mTOR inhibitor iseverolimus.
 52. The method of claims 46-50, wherein the age relatedcondition is selected from the group consisting of sarcopenia, skinatrophy, muscle wasting, brain atrophy, atherosclerosis,arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis,high blood pressure, erectile dysfunction, dementia, Huntington'sdisease, Alzheimer's disease, cataracts, age-related maculardegeneration, prostate cancer, stroke, diminished life expectancy,impaired kidney function, and age-related hearing loss, aging-relatedmobility disability (e.g., frailty), cognitive decline, age relateddementia, memory impairment, tendon stiffness, heart dysfunction such ascardiac hypertrophy and systolic and diastolic dysfunction,immunosenescence, cancer, obesity, and diabetes.
 53. A method oftreatment according to any preceding use or combination.